Neurotransmitters and Drug Abuse

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Chapter 21 Neurotransmitters and Drug Abuse

This chapter recapitulates and expands information on the major neurotransmitters’ synthesis, metabolism, functional anatomic pathways, and mechanism of action. In addition, it reviews their altered activity in important neurologic disorders and treatments. With a few exceptions, the chapter restricts the discussion of neurotransmitters’ role to central nervous system (CNS) diseases and does not address psychopharmacology. This chapter reviews the following neurotransmitters:

• Monoamines:

• Catecholamines: dopamine, norepinephrine, and epinephrine
• Indolamines: serotonin

• Acetylcholine (ACh)

• Neuropeptides:

• Inhibitory amino acids: gamma-aminobutyric acid (GABA), glycine
• Excitatory amino acids: glutamate

• Nitric oxide

Monoamines

Dopamine

Synthesis and Metabolism

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Neurologists hold dopamine synthesis in pre-eminent regard and treasure each substrate, synthetic and metabolic enzyme, and byproduct. They capitalize on its synthesis when they treat Parkinson disease and several other neurologic illnesses.

Dopamine synthesis begins with the amino acid phenylalanine, and proceeds sequentially through tyrosine, DOPA, and then dopamine. Tyrosine hydroxylase is the rate-limiting enzyme in this pathway. Another important enzyme is DOPA decarboxylase, which decarboxylates DOPA to form dopamine. That same enzyme acts on both naturally occurring DOPA and L-dopa (levodopa), the Parkinson disease medicine.

Several different processes terminate dopamine activity at the synapse. The primary one consists of dopamine reuptake back into the presynaptic neuron. In another termination process, two different enzymes metabolize dopamine. Catechol-O-methyltransferase (COMT), mostly an extracellular enzyme, and monoamine oxidase (MAO), mostly an intracellular enzyme, each metabolize dopamine. Certain medicines for Parkinson disease and other conditions that result from dopamine deficiency preserve dopamine by inhibiting these enzymes (see later).

When COMT and MAO metabolize dopamine, the main product consists of homovanillic acid. The concentration of this metabolite in the cerebrospinal fluid (CSF) roughly corresponds to dopaminergic activity in the brain.

Anatomy

Three “long dopamine tracts” hold the greatest clinical importance in neurology:

1. The nigrostriatal tract, the major component of the extrapyramidal motor system, synthesizes most dopamine in the brain. This tract projects from the substantia nigra, the crescentic pigmented nuclei in the midbrain (Fig. 21-1), to the predominantly D2 receptors of the striatum (the caudate nucleus and putamen [see Chapter 18]).

2. The mesolimbic tract projects from the ventral tegmental area, situated in the inferior medial portion of the midbrain, to the amygdala and other portions of the limbic system. Its receptors are predominantly D4. The mesolimbic tract appears to propagate the positive symptoms of psychosis, whereas antipsychotic agents, by blocking dopamine transmission in this tract, reduce dopamine activity in the limbic system and thus suppress psychotic symptoms.

3. The mesocortical tract also projects from the ventral tegmental area, but it terminates primarily in the frontal cortex. It also terminates in the cingulate and prefrontal gyrus, creating an overlap with the mesolimbic system. The mesocortical tract likely propagates negative symptoms of psychosis. In addition, because illicit drugs affect both the mesolimbic and mesocortical tracts, these tracts serve as the neural substrates for drug addiction.

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FIGURE 21-1 Coronal view of the midbrain, which gives rise to several dopamine-producing tracts – including the nigrostriatal, mesolimbic, and mesocortical. The nigrostriatal tract begins in the substantia nigra (SN), the large curved black structures in the base of the midbrain (see Fig. 18-2). The red nuclei (RN), which receive cerebellar outflow tracts, sit above the substantia nigra. The upper portion of the midbrain, the tectum (Latin, roof; tego, to cover), contains the aqueduct of Sylvius (A), which is surrounded by the periaqueductal gray matter, and the superior colliculi (SC). The oculomotor nuclei (III), which give rise to the third cranial nerves, lie midline, just below the aqueduct.

In addition to these long tracts, several “short dopamine tracts” hold clinical significance. The tubero-infundibular tract connects the hypothalamic region with the pituitary gland. Dopamine in this tract suppresses prolactin secretion and thus inhibits galactorrhea. (Its absence or blockade of its activity promotes galactorrhea.) Another short tract exists within the retina.

Receptors

Although neuroscientists have identified numerous dopamine receptors, the most important ones are the D1, D2, and closely related receptors. The D1 receptor group includes both the D1 and D5 receptors. The D2 receptor group includes the D2, D3, and D4 receptors. These dopamine receptors are coupled to guanine nucleotide-binding protein (G proteins). Because they exert their effects through second messengers, such as cyclic AMP, neuroscientists consider them “slow” neurotransmitters.

The D1 and D2 receptors remain the most important in extrapyramidal system disorders (Table 21-1). Both types of these receptors are plentiful in the striatum, but D1 receptors are more abundant and more widely distributed.

TABLE 21-1 Pharmacology of D1 and D2 Receptors

  D1 D2
Effect of stimulation on cyclic AMP production Increased Decreased
Greatest concentrations Striatum, limbic system, and cerebral cortex Striatum, substantia nigra
Effect of dopamine Weak agonist Strong agonist
Effects of dopamine agonists Vary with agonist Strong
Effect of phenothiazines Strong antagonist Strong antagonist
Effect of butyrophenones Weak antagonists Strong antagonists
Effect of clozapine Weak antagonist Weak antagonist

When antipsychotics block D2 receptors, the reduced dopamine activity induces parkinsonism, raises prolactin production (inducing galactorrhea), and places patients at risk for tardive dyskinesia. Some atypical antipsychotic agents, particularly risperidone and its active metabolite paliperidone (Invega), raise prolactin serum concentration and induce galactorrhea. Even nonpsychiatric medications that decrease dopamine activity, such as metoclopramide (Reglan), which blocks D2 receptors, and tetrabenazine (see Chapter 18), which depletes dopamine from its presynaptic storage vesicles, increase prolactin serum concentration and induce parkinsonism. In contrast, clozapine, which shows little D2 receptor affinity, does not lead to either of these problems.

Physicians should bear in mind that finding an elevated serum prolactin level does not always indicate use of a dopamine-blocking medication or the presence of a pituitary tumor (see Chapter 19). The most common cause of serum prolactin elevation is pregnancy.

Conditions due to Reduced Dopamine Activity

Phenylketonuria.

Deficiencies in dopamine synthesis enzymes underlie several well-known neurologic disorders. A congenital absence of phenylalanine hydroxylase, the initial enzyme in the synthetic pathway, leads to phenylketonuria (PKU). In PKU, an autosomal recessive disorder, a lack of phenylalanine hydroxylase results in the accumulation of phenylalanine. As a result, alternative metabolic pathways convert the excess phenylalanine to phenylketones, which are excreted and readily detectable in the urine. The presence of phenylketones in the urine gave rise to the name of the illness. Obstetric services routinely screen neonates for this disorder.

Unless detected and corrected, PKU leads to severe mental retardation and epilepsy. In addition, because the enzyme deficiency prevents synthesis of tyrosine, which is a melanin precursor, affected children lack pigment in their hair and irises. The absence of color gives them a fair complexion, blond hair, and blue eyes. Eczema is another characteristic.

If research on gene replacement therapy succeeds, replacement of phenylalanine hydroxylase will become practical. Until then, affected individuals must remain on a phenylalanine-free diet.

Dopamine-Responsive Dystonia.

Dopamine-responsive dystonia (DRD), a multifactorial genetic deficiency of both phenylalanine hydroxylase and tyrosine hydroxylase, leads to a dopamine deficiency in children. Characteristically, in the afternoon, after dopamine stores have been depleted, affected children develop dystonia or other abnormal involuntary movements that mimic cerebral palsy. In the morning, after the brain has replenished dopamine stores, these children have regained full mobility and show no involuntary movements. Thus, a diurnal fluctuation of an involuntary movement disorder characterizes DRD.

L-dopa, even in small amounts, inserts itself into the synthetic pathway. It bypasses the enzyme deficiencies and allows the nigrostriatal neurons to synthesize enough dopamine to reverse the symptoms (see Chapter 18). Small doses of L-dopa restore normal mobility throughout the entire day. The response to L-dopa is so reliable that it serves as a preliminary diagnostic test for DRD.

Parkinson Disease.

In Parkinson disease, the progressive degeneration of dopamine-synthesizing neurons in the substantia nigra leads to increasingly severe dopamine deficiency. Neurologists treating Parkinson disease patients attempt to enhance dopamine activity in three ways.

1. As a first-line treatment, they administer the dopamine precursor L-dopa. As long as enough nigrostriatal (presynaptic) neurons remain intact, DOPA decarboxylase converts L-dopa to sufficient quantities of dopamine to reverse the symptoms (see Fig. 18-3).

2. As the disease progresses, the presynaptic neurons degenerate beyond the stage where they can synthesize, store, and appropriately release dopamine. At this time, if not as a first-line treatment, neurologists add a dopamine receptor agonist to the medication regimen. As a substitute or supplement for L-dopa, dopamine agonists, such as pramipexole, ropinirole, and apomorphine, stimulate dopamine receptors. That stimulation replicates dopamine’s effect and alleviates symptoms.

3. As long as dopamine synthesis continues, neurologists prescribe medicines that slow L-dopa metabolism in the periphery but allow DOPA to continue forming dopamine centrally. Working in that way, two Parkinson disease medications – carbidopa and entacapone – inactivate enzymes that metabolize L-dopa and thereby enhance dopamine activity (see Fig. 18-11). Carbidopa inactivates DOPA decarboxylase. Entacapone inhibits COMT, which normally inactivates L-dopa by converting it to 3-O-methyldopa. Both enzyme inhibitors act almost entirely outside the CNS because they have little ability to penetrate the blood–brain barrier. Therefore, they do not interfere with basal ganglia dopamine synthesis. Giving these enzyme inhibitors along with L-dopa enables small doses of L-dopa to be effective. Moreover, the small doses of dopamine reduce its systemic side effects, such as nausea, vomiting, cardiac arrhythmias, and hypotension.

Commercial preparations combine enzyme inhibitors with L-dopa to prevent its metabolism outside the brain. For example, Sinemet combines carbidopa with L-dopa and Stalevo adds entacapone to carbidopa and L-dopa. As compared to L-dopa alone, L-dopa–carbidopa combinations, such as Sinemet (Latin, sine without, em vomiting), almost completely eliminate the side effects of nausea and vomiting.

Another therapeutic option entails protecting dopamine itself from metabolic enzymes, particularly MAO. Selegiline (deprenyl [Eldepryl]) inhibits MAO-B, one of the two major forms of MAO. Selegiline readily penetrates the blood–brain barrier and, by inhibiting MAO-B, preserves both naturally occurring and L-dopa-derived dopamine. Another advantage of selegiline is that its metabolism yields small amounts of amphetamine and methamphetamine that partially offset Parkinson disease-related fatigue and depression.

Although antidepressant MAO inhibitors inactivate both MAO-A and MAO-B or only MAO-A, selegiline inhibits only MAO-B. In its usual therapeutic dose (≤10 mg) for Parkinson disease treatment, selegiline preserves dopamine but does not place patients, even if they eat tyramine-containing foods, at risk of a hypertensive crisis. Nevertheless, neurologists cautiously use serotonin-enhancing medicines, such as triptans for headaches and selective serotonin reuptake inhibitors for Parkinson disease-induced depression, in patients taking selegiline.

Medication-Induced Parkinsonism.

In contrast to Parkinson disease, where presynaptic neurons have degenerated, medication-induced parkinsonism usually results from blockade of basal ganglia D2 receptors. This distinction holds great clinical importance when a patient who is under treatment with an antipsychotic agent develops Parkinson disease symptoms. Giving L-dopa at the same time that antipsychotic agents block D2 receptors may still increase dopamine synthesis, but the dopamine will not affect the receptors or correct the symptoms. More importantly, excess dopamine will stimulate frontal cortex and limbic system dopamine receptors: It may therefore provoke or exacerbate a psychosis. Thus, when a patient who has been treated with an antipsychotic agent – even as recently as 1 month – appears to have developed Parkinson disease, physicians should generally maintain that the patient has iatrogenic parkinsonism; search for alternative diagnoses that can cause both psychosis and parkinsonism, such as dementia with Lewy bodies or Wilson disease; and postpone administering medicines that enhance dopamine.

Neuroleptic-Malignant Syndrome.

An acute absence of dopamine activity causes the parkinson-hyperpyrexia or central dopaminergic syndrome, which neurologists still call the neuroleptic-malignant syndrome (NMS) (see Chapter 6). Administering dopamine agonists may compensate for the absence of dopamine activity and alleviate some of the symptoms, but treatment is generally supportive. Patients usually require parenteral treatment, such an intramuscular injections of the dopamine agonist apomorphine, because the severe muscle rigidity prevents their swallowing pills and the urgency of the situation demands treatment with rapid onset of action.

Conditions due to Excessive Dopamine Activity

Of the several mechanisms that might lead to excessive dopamine activity, the most common is the administration of L-dopa. Cocaine and amphetamine also cause excessive dopamine activity by provoking dopamine release from its presynaptic storage sites and then blocking its reuptake. Some psychiatric medications, such as bupropion (Wellbutrin), also block dopamine reuptake. In a different mechanism, possibly underlying some cases of tardive dyskinesia, increased sensitivity of the postsynaptic receptors results in excessive dopaminergic activity.

Whatever the cause, excessive dopamine activity produces a range of side effects from psychosis to hyperkinetic movement disorders. For example, Parkinson disease patients who take excessive L-dopa may develop visual hallucinations, paranoia, and thought disorders that can reach psychotic proportions. Excessive dopamine activity also produces hyperkinetic movement disorders, such as chorea, tremor, tics, dystonia, and the oral-buccal-lingual variety of tardive dyskinesia.

As a less dramatic example of the effects of excessive dopamine, some Parkinson disease patients become overly involved with stimulating activities, such as sex and gambling. In these cases, neurologists diagnose the dopamine dysregulation syndrome or impulse control disorder (see Chapter 18). They usually ascribe the aberrant behavior to dopamine-induced novelty seeking and inattention.

On the other hand, with a small increase in dopamine activity, as occurs with bupropion treatment, individuals enjoy a sense of well-being. That sensation, however, represents a mere glimmer of a cocaine or amphetamine rush.

In addition to their effects on movements, dopamine and its agonists, acting through the tubero-infundibular tract, inhibit prolactin release from the pituitary gland. Neurologists and endocrinologists prescribe bromocriptine and cabergoline, both dopamine agonists, to shrink pituitary adenomas and suppress their prolactin secretion. In the opposite situation, dopamine receptor blockade of the tubero-infundibular tract by typical neuroleptics and risperidone – but not clozapine or quetiapine – may enhance prolactin release and thereby raise its serum concentration. Patients taking these medicines often report decreased sexual drive and even galactorrhea.

Probably stemming from CNS rather than peripheral nervous system (PNS) dysfunction, habitual cocaine users often experience a paresthesia of ants crawling on or under their skin. Neurologists call this sensation a formication (Latin, formica, ant), but cocaine users call it “coke bugs.”

Norepinephrine and Epinephrine

Synthesis and Metabolism

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After the synthesis of dopamine, continuation of the pathway yields norepinephrine and then epinephrine. These neurotransmitters, as well as dopamine, are catecholamines, a subcategory of the monoamines. As with dopamine synthesis, tyrosine hydroxylase remains the rate-limiting enzyme in their synthesis. Also, as with dopamine activity, reuptake and metabolism by COMT and MAO terminate their actions. In contrast to dopamine metabolism, most norepinephrine metabolism takes place outside the CNS. Moreover, its primary metabolic byproduct, which appears in the urine, is vanillylmandelic acid.

Anatomy

CNS norepinephrine synthesis takes place primarily in the locus ceruleus, which is located in the dorsal portion of the pons (Fig. 21-2). Neurons from the locus ceruleus project to the cerebral cortex, limbic system, and reticular activating system. In addition, whereas dopamine tracts remain confined to the brain, norepinephrine tracts project down into the spinal cord.

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FIGURE 21-2 Coronal view of the pons, fourth ventricle (IV), and cerebellum. This portion of the brainstem contains paired locus ceruleus (diagonal arrow) and dorsal raphe nucleus (horizontal arrow). The locus ceruleus, which sits lateral and inferior to the fourth ventricle, gives rise to norepinephrine tracts. The dorsal raphe nucleus gives rise to serotonin tracts that spread cephalad, to the diencephalon and cerebrum. A caudal raphe nucleus, in the pons and medulla (not pictured), gives rise to serotonin tracts that spread to the spinal cord.

Also unlike dopamine, norepinephrine serves as the neurotransmitter for the sympathetic nervous system’s postganglionic neurons. In the adrenal gland, a synthetic pathway converts norepinephrine to epinephrine.

Receptors

Norepinephrine receptors are located in the cerebral cortex, brainstem, and spinal cord. The α2 and β2 receptors, termed “autoreceptors,” are situated on presynaptic neurons. Through a feedback mechanism, these presynaptic receptors modulate norepinephrine synthesis and release (Fig. 21-3). Postsynaptic receptors are also of two varieties, α1 and β1, and they produce varied and sometimes almost opposite effects (Table 21-2).

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FIGURE 21-3 In norepinephrine and epinephrine synapses, the postsynaptic neuron has α1 and β1 receptors, which initiate the sympathetic “fight or flight” response. The presynaptic neuron has α2 and β2 autoreceptors that modulate sympathetic responses (see Table 21-2).

TABLE 21-2 Pharmacology of Epinephrine and Norepinephrine Receptors

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*See Fig. 21-3.

Conditions due to Alterations in Norepinephrine Activity

In Parkinson disease, the locus ceruleus, just like the substantia nigra, degenerates and loses its pigment. Loss of norepinephrine synthesis often leads to orthostatic hypotension, sleep disturbances, and depression.

In the opposite situation, excessive stimulation of β2-adrenergic sites leads to tremor and bronchodilatation. For example, isoproterenol and epinephrine, particularly when used for asthma, cause tremor as they alleviate bronchospasm. Conversely, β-blockers, which are contraindicated in asthma patients, suppress essential tremor (see Chapter 18).

Although rare, pheochromocytomas are the best-known example of excessive norepinephrine and epinephrine activity. These tumors secrete norepinephrine or epinephrine continually or in erratic bursts. Depending on the pattern, patients have hypertension, tachycardia, and sometimes convulsions.

Serotonin

Synthesis and Metabolism

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Serotonin (5-hydroxytryptamine, 5-HT) is another monoamine, but an indolamine rather than a catecholamine. The synthesis of serotonin parallels the synthesis of dopamine – hydroxylation followed by decarboxylation. Although the rate-limiting enzyme in serotonin synthesis is tryptophan hydroxylase rather than tyrosine hydroxylase, hydroxylation remains the rate-limiting step in its synthesis. Also, reuptake and, to a lesser extent, oxidation terminate serotonin activity.

MAO-A metabolizes serotonin to 5-hydroxyindoleacetic acid (5-HIAA). Although platelets, gastrointestinal cells, and other nonneurologic cells synthesize more than 98% of the body’s total serotonin, that serotonin does not penetrate the blood–brain barrier. Thus, CSF concentrations of HIAA reflect CNS serotonin activity. Other enzymes metabolize serotonin to melatonin.

Anatomy

Serotonin-producing CNS neurons reside predominantly in the dorsal raphe nuclei, which are located in the midline of the dorsal midbrain and pons (see Figs 21-2 and 18-2). Serotonin tracts project rostrally (upward) to innervate the cortex, limbic system, striatum, and cerebellum. They also innervate intracranial blood vessels, particularly those around the trigeminal nerve.

Other serotonin-producing nuclei, the caudal raphe nuclei, are located in the midline of the lower pons and medulla. They project caudally (downward) to the dorsal horn of the spinal cord to provide analgesia (see Chapter 14).

Receptors

Studies have identified numerous CNS serotonin receptors (5-HT1–5-HT7) and many subtypes. Serotonin receptors differ in their function, response to medications, effect on second-messenger systems, and excitatory or inhibitory capacity. Several serotonin receptors, such as 5-HT1D, are presynaptic autoreceptors that suppress serotonin synthesis or block its release. In an almost ironic relationship, 5-HT1 promotes production of adenyl cyclase and is inhibitory, but 5-HT2 promotes production of phosphatidyl inositol and is excitatory. Other serotonin receptors are usually G-protein-linked and excitatory.

Conditions due to Alterations in Serotonin Activity

Serotonin plays a major role in the daily sleep–wake cycle. The activity of serotonin-producing cells reaches its highest level during arousal, drops to quiescent levels during slow-wave sleep, and disappears during rapid eye movement (REM) sleep (see Chapter 17).

Depression is the disorder most closely associated with low serotonin activity. In the extreme, low postmortem CSF concentrations of HIAA, the serotonin metabolite, characterize suicides by violent means. This finding, one of the most consistent in biologic psychiatry, reflects low CNS serotonin activity. Similarly, individuals with poorly controlled violent tendencies, even those without a history of depression, have low concentrations of CSF HIAA.

Serotonin levels are also decreased in individuals with Parkinson or Alzheimer disease. Among Parkinson disease patients, the decrease is more pronounced in those with comorbid depression.

Sumatriptan and other triptans, a mainstay of migraine therapy, are selective 5-HT1D receptor agonists. Once stimulated, these serotonin receptors inhibit the release of pain-producing vasoactive and inflammatory substances from trigeminal nerve endings.

A series of powerful antiemetics, including dolasetron (Anzemet) and ondansetron (Zofran), are 5-HT3 antagonists. By affecting the medulla’s area postrema, one of the few areas of the brain unprotected by the blood–brain barrier, they reduce chemotherapy-induced nausea and vomiting. Similarly, second-generation antipsychotics typically act as antagonists of 5-HT2A as well as D2 receptors.

Although increased serotonin activity is often therapeutic, excessive activity poses a danger. For example, combinations of medicines that simultaneously block serotonin reuptake and inhibit its metabolism lead to serotonin accumulation. These combinations may cause toxic levels and the serotonin syndrome (see Chapters 6 and 18).

In another situation characterized by excessive serotonin activity, LSD (D-lysergic acid diethylamide) induces hallucinations and euphoria by stimulating 5-HT2 receptors. Similarly, “ecstasy” (methylenedioxymethamphetamine [MDMA]), although it also stimulates dopaminergic activity, greatly enhances serotonin activity by triggering a presynaptic outpouring. Ecstasy’s effects surpass LSD’s in stimulating serotonin activity.

Acetylcholine

Synthesis and Metabolism

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The combination of acetyl coenzyme A and choline form ACh. Although ACh synthesis depends on the enzyme choline acetyltransferase (ChAT), the rate-limiting factor is the substrate, choline.

Unlike monoamines, ACh does not undergo reuptake. Instead, cholinesterase (the common contraction of acetylcholinesterase) terminates its action in the synaptic cleft. This enzyme hydrolyzes ACh back to acetyl coenzyme A and choline.

Anatomy

In the CNS, most ACh tracts originate in the nucleus basalis of Meynert (also known as the substantia innominata) and adjacent nuclei situated in the basal forebrain (a rostral portion of the brainstem) (Fig. 21-4). These nuclei project their cholinergic tracts throughout the cerebral cortex but particularly to the hippocampus, amygdala, and cortical association areas. In addition, ACh serves as the autonomic nervous system and neuromuscular junction neurotransmitter (see Fig. 6-1).

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FIGURE 21-4 This coronal view of the diencephalon, the uppermost brainstem region, shows the nucleus basalis of Meynert, which is situated adjacent to the third ventricle and the hypothalamus.

Receptors

ACh receptors fall into two categories, nicotinic and muscarinic. One or the other predominates in either the cerebral cortex or the neuromuscular junction, produces excitatory or inhibitory actions, and remains vulnerable to different blocking agents (Table 21-3).

TABLE 21-3 Cerebral Cortex and Neuromuscular Junction Acetylcholine (ACh) Receptors

  Cerebral Cortex Neuromuscular Junction
Predominant ACh receptors Muscarinic Nicotinic
Main action Excitatory or inhibitory Excitatory
Agents that block receptor Atropine, scopolamine Curare, α-bungarotoxin

Conditions due to Reduced ACh Activity at the Neuromuscular Junction

In the PNS, decreased neuromuscular ACh activity – from either impaired presynaptic ACh release or blockade of postsynaptic ACh receptors – leads to muscle paralysis. Conditions that interfere with ACh activity have different etiologies and induce distinct patterns of weakness. For example, in Lambert–Eaton syndrome, the paraneoplastic disorder, antibodies impair the release of ACh from presynaptic neurons and cause weakness of limbs (see Chapters 6 and 19). Botulinum toxin also impairs ACh release from the presynaptic neuron; when ingested as a food poison (botulism), it primarily causes potentially fatal weakness of ocular, facial, limb, and respiratory muscles. When injected into affected muscles for treatment of focal dystonia, medicinal botulinum toxin inhibits forceful muscle contractions because it slows or prevents ACh release from the presynaptic neuron at the neuromuscular junction (see Chapter 18).

At the postsynaptic neuron of the neuromuscular junction, curare, other poisons, and antibodies, such as those associated with myasthenia gravis, each block ACh receptors. The pattern of weakness in myasthenia gravis is distinctive: Patients have asymmetric paresis of the extraocular and facial muscles, but not the pupils. To overcome the ACh receptor blockade in myasthenia gravis, neurologists administer anticholinesterase (the common contraction of antiacetylcholinesterase) medications, such as edrophonium (Tensilon), pyridostigmine, and physostigmine, to inhibit cholinesterase and thereby reduce the breakdown of ACh in the synaptic cleft (see Chapter 6 and Fig. 7-6). The reliability of edrophonium in temporarily reversing myasthenia-induced paralysis has led to the “Tensilon test” (see Fig. 6-4).

Conditions due to Reduced ACh Activity in the CNS

In Alzheimer disease, the cerebral cortex has markedly reduced cerebral ACh concentrations, ChAT activity, and muscarinic receptors (see Chapter 7). In addition, some nicotinic receptors are depleted.

To counteract the ACh deficiency in Alzheimer disease, neurologists have attempted several strategies to enhance its synthesis or slow its metabolism. In hopes of driving ACh synthesis, they have administered precursors, such as choline and lecithin (phosphatidylcholine). Although analogous to providing a dopamine precursor (L-dopa) in Parkinson disease treatment, this strategy failed in reversing the symptoms of Alzheimer disease. A complementary strategy has been to slow ACh metabolism by administering long-acting cholinesterase inhibitors that cross the blood–brain barrier. Several such cholinesterase inhibitors, such as donepezil, may slow the progression of dementia in Alzheimer disease and several other illnesses (see Chapter 7).

Reduced ACh concentrations also characterize trisomy 21, which shares many clinical and physiologic features of Alzheimer disease. Also, the cortex in Parkinson disease and progressive supranuclear palsy (PSP) has reduced ACh concentrations.

Many studies have indicated that an absolute ACh deficiency or, compared to dopamine activity, a relative ACh deficiency causes delirium. Reduced ACh activity leading to cognitive impairment or delirium may occasionally have an iatrogenic basis. For example, scopolamine and other drugs that block muscarinic ACh receptors interfere with memory, learning, attention, and level of consciousness – even when given to normal individuals. In fact, scopolamine, which readily crosses the blood–brain barrier, induces a transient amnesia that has been a laboratory model for Alzheimer disease dementia.

Anticholinergic Syndrome

Chlorpromazine, other typical antipsychotic agents, and tricyclic antidepressants may block muscarinic ACh receptors and cause physical anticholinergic side effects, including drowsiness, dry mouth, urinary hesitancy, constipation, and accommodation paresis (see Chapter 12). Anticholinergic activity may also rise in individuals taking nonpsychiatric medicines, such as atropine, scopolamine, benztropine, and trihexyphenidyl. With enough anticholinergic activity, individuals develop the anticholinergic syndrome: dilated pupils, elevated pulse and blood pressure, dry skin and hyperthermia, and delirium that may progress to coma. In this situation physicians may administer physostigmine, an anticholinesterase that crosses the blood–brain barrier, to restore ACh activity.

In a related but interesting correlation, antipsychotic agents with the greatest muscarinic anticholinergic side effects, namely clozapine and olanzapine, have among the least tendency to produce parkinsonism and other extrapyramidal side effects. Conversely, antipsychotic agents with the least anticholinergic side effects have the greatest tendency to produce those extrapyramidal side effects.

Conditions due to Excessive ACh Activity

ACh intoxication takes the form of a massive, predominantly muscarinic parasympathetic discharge. Its primary features consist of bradycardia, hypotension, miosis, and a characteristic outpouring of bodily fluids in the form of excess lacrimation, salivation, bronchial secretions, and diarrhea. Depending on the poison, dose, and route of entry, victims may show signs of CNS involvement, which may include delirium, slurred speech, and seizures. Sometimes they may also show signs of PNS involvement, such as generalized flaccid paresis and fasciculations.

Medications, homicide, suicide, or accidents at home or work may lead to ACh poisoning. In most cases, inactivation of cholinesterase leads to a toxic accumulation of unmetabolized ACh in the brain, autonomic ganglia, and neuromuscular junction. For example, patients with dementia who accidentally take too many donepezil pills or apply rivastigmine patches without removing the old ones may eliminate their cholinesterase and allow an excess of unmetabolized ACh to accumulate. Similarly, eating certain mushrooms will also cause ACh toxicity. Individuals may suffer from exposure to common organophosphorus insecticides, such as parathion and Malathion, or they may swallow a Latin American rat poison, tres pasitos, which looks like grains of rice. Ingestion of these poisons may be the result of suicide or homicide attempts as well as occupational exposure. Similarly, many poison gases, such as the terrorist gas sarin, raise ACh concentrations to toxic levels.

Supporting vital functions, especially respiration, is essential. The specific treatment of ACh poisoning from organophosphate ingestion, which is probably the most common scenario, consists of the administration of atropine, which is a competitive inhibitor of ACh at muscarinic receptors, to reverse the parasympathetic overactivity, and pralidoxime to reactivate cholinesterase activity. Health care workers should remain aware that the poison often saturates the clothing of victims.

Neuropeptides

Gamma-Aminobutyric Acid – An Inhibitory Amino Acid Neurotransmitter

Synthesis and Metabolism

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GABA and, to a lesser extent, glycine are the brain’s major inhibitory neurotransmitters. Glutamate, decarboxylated by the enzyme glutamate decarboxylase (GAD), forms GABA. An important aspect of the synthesis is that GAD requires vitamin B6 (pyridoxine) as a cofactor. GABA undergoes reuptake or metabolism by several enzymes.

Anatomy

Reflecting its widespread and critical role in inhibition, GABA is distributed throughout the entire CNS. However, it is concentrated in the striatum, hypothalamus, spinal cord, and temporal lobe.

Receptors

The two GABA receptors, GABAA and GABAB, are complex molecules. GABAA receptors, which are more numerous and important than GABAB receptors, are gated to various molecules called ligands. The receptors have binding sites for benzodiazepines, barbiturates, alcohol, and some antiepileptic drugs (AEDs).

When activated by these ligands, GABAA receptors open chloride channels, and this allows negatively charged chloride ions (Cl–) to flow into the cell. The influx of these negatively charged ions into neurons lowers (makes more negative) their resting potential, which is normally –70 mV. GABA-induced lowering of the resting potential, which hyperpolarizes the membrane, has an inhibitory effect on the cell. Because of the rapidity of this hyperpolarization, which is based on changes in the permeability of ion channels, neuroscientists consider GABA and several other neurotransmitters as “fast.”

The GABAB receptor, a G protein coupled to calcium and potassium channels, is also inhibitory. Baclofen, which counteracts spasticity, dystonia, and neuropathic pain, binds to this receptor. In contrast to the large numbers of ligands that bind to the GABAA receptor, baclofen is one of the few that binds to the GABAB receptor. Other medicines that alleviate spasticity act through different mechanisms. For example, tizanidine (Zanaflex) acts as an α2-adrenergic agonist and dantrolene (Dantrium) reduces muscle contraction by acting directly on muscles.

Conditions due to Alterations in GABA Activity

GABA deficiency is characterized by a lack of inhibition, which leads to excessive activity. For example, in Huntington disease, depleted GABA reduces inhibition in the basal ganglia, presumably leading to excessive involuntary movement, typically chorea. Tetanus and strychnine poisoning each illustrate the effects of decreased GABA activity (see later).

In the stiff-person syndrome, formerly known as the stiff-man syndrome, anti-GAD antibodies reduce GABA synthesis. The reduced GABA activity in this disorder leads to muscle stiffness and gait impairment that physicians might mistake for catatonia or an acute dystonic reaction to antipsychotic agents; however, the symptoms are not so acute or severe that neurologists might diagnose tetanus or strychnine poisoning. Neurologists usually diagnose the stiff-person syndrome by finding anti-GAD antibodies in the serum and CSF. In many cases, the stiff-person syndrome is associated with an underlying neoplasm, such as breast cancer, or various autoimmune diseases. Whatever the cause, immunomodulation and diazepam usually alleviate the stiffness.

Diets deficient in pyridoxine, the cofactor for GAD, impair GABA synthesis and cause seizures. Likewise, overdose of isoniazid (INH), which interferes with pyridoxine, occasionally leads to seizures. In both cases, the seizures respond to intravenous pyridoxine.

Several AEDs are effective, in part, because they increase GABA activity. For example, valproate (Depakote) increases brain GABA concentration. Tiagabine (Gabitril) inhibits GABA reuptake. Topiramate (Topamax) enhances GABAA receptor activity. Vigabatrin (Sabril) increases GABA concentrations by reducing its metabolic enzyme, GABA-transaminase.

In a different situation, flumazenil, a benzodiazepine antagonist, blocks the actions of GABA at its receptor and reverses benzodiazepine-induced stupor and hepatic encephalopathy. In the case of hepatic encephalopathy, flumazenil presumably displaces false, benzodiazepine-like neurotransmitters from GABA receptors (see Chapter 7).

Glycine – Another Inhibitory Amino Acid Neurotransmitter

Synthesis, Metabolism, and Anatomy

Glycine, while a simple amino acid and not essential to the human diet, acts not only as a powerful inhibitory neurotransmitter but also paradoxically as a co-agonist or modulator of the excitatory neurotransmitter glutamate at NMDA receptors. The enzyme hydroxymethyl transferase converts the amino acid serine to glycine. Several different metabolic pathways inactivate it.

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Glycine’s inhibitory activity affects the ventral horn of the spinal cord, which is the site of motor neurons, and the brainstem. Under normal circumstances, glycine provides inhibition of muscle tone that balances the excitation of muscle tone provided by other neurotransmitters.

Conditions due to Alterations in Glycine Activity

Reduced glycine activity characterizes tetanus and strychnine poisoning. In both conditions, loss of inhibitory activity causes patients to suffer from unrelenting powerful muscle contractions. In tetanus (see Chapter 6), the toxin (tetanospasmin) prevents the presynaptic release of glycine and GABA. Due mostly to the loss of glycine-induced muscle inhibition, tetanus patients suffer “tetanic contractions” of limb, facial, and jaw muscles, typically manifest as “lockjaw.” In a different mechanism of action but with similar results, strychnine blocks the postsynaptic glycine receptor. Strychnine poisoning leads to fatal limb, larynx, and trunk muscle contractions.

Glutamate – An Excitatory Amino Acid Neurotransmitter

Synthesis, Metabolism, and Anatomy

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Glutamate, a simple amino acid synthesized from glutamine, is the most important excitatory neurotransmitter. Reuptake into presynaptic neurons and adjacent support cells terminates glutamate activity. To a lesser extent, glutamate undergoes nonspecific metabolism. Its tracts project throughout the brain and spinal cord.

Aspartate is another excitatory amino acid. However, compared to glutamate, its anatomy and clinical importance are less well established.

Receptors

Of several glutamate receptors, N-methyl-D-aspartate (NMDA) is the most important. It has binding sites for glycine, phencyclidine (PCP), and a PCP congener, ketamine (see later). Through its interactions with NMDA receptors, which regulate calcium channels, glutamate acts as a fast neurotransmitter.

Conditions due to Alterations in NMDA Activity

Excessive NMDA activity floods the neuron with potentially lethal concentrations of calcium and sodium in several disorders. Through this process, excitotoxicity, glutamate–NMDA interactions lead to neuron death through apoptosis. Excitotoxicity may be intimately involved in the pathophysiology of epilepsy, stroke, neurodegenerative diseases (such as Parkinson and Huntington diseases), head trauma, and, conceivably, schizophrenia. In certain paraneoplastic syndromes, particularly one triggered by ovarian teratomas in young women, antibodies directed toward NMDA receptors create an autoimmune limbic encephalitis (see Chapter 19).

Consequently, one approach to stemming the progression of neurodegenerative diseases has been to use medicines that block glutamate–NMDA interactions. Despite this rationale, such medicines provide only a modicum of neuroprotection. For example, riluzole (Rilutek), which decreases glutamate activity, only transiently interrupts the progression of amyotrophic lateral sclerosis. Similarly, memantine (Namenda), an NMDA receptor antagonist, blocks its deleterious excitatory neurotransmission and slows the progression of Alzheimer disease for approximately only 6 months. Also, the AEDs, gabapentin and lamotrigine, are glutamate antagonists.

Despite the benefit of blocking glutamate in various diseases, deficient NMDA activity can also be harmful. For example, PCP and ketamine may block the NMDA calcium channel and cause psychosis.

Other Neuropeptides

Endorphins, enkephalins, and substance P, which are situated in the spinal cord and brain, provide endogenous analgesia in response to painful stimuli (see Chapter 14). Substance P and, to a lesser degree, other neuropeptides are depleted in Alzheimer disease. The other neuropeptides that are reduced include somatostatin, cholecystokinin, and vasoactive intestinal peptide.

A pair of neuropeptides, hypocretin-1 and -2, also known as orexin A and B, are excitatory neurotransmitters that play a crucial – but an ill-defined – role in locomotion, metabolism, appetite, and the sleep–wake cycle (see Chapter 17). Synthesized in the hypothalamus, where they are cleaved from a large precursor protein, these neuropeptides increase during wakefulness and REM sleep, and decrease during non-REM sleep. Unlike normal individuals, narcolepsy patients have little or no hypocretin in their CSF and their hypothalamus is devoid of hypocretin-producing cells.

Nitric Oxide

Synthesis and Metabolism

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Nitric oxide (NO), the product of a complex synthesis, is an important neurotransmitter for endothelial cells and the immunologic system. NO should not be confused with nitrous oxide (N2O), which is a gaseous anesthetic (“laughing gas”). N2O, when inhaled daily as a form of drug abuse, leads to vitamin B12 deficiency, which results in cognitive impairment and spinal cord damage (combined system disease).

Important in many roles, NO inhibits platelet aggregation, dilates blood vessels, and boosts host defenses against infections and tumors. From a neurologic viewpoint, its main functions include regulating cerebral blood flow and facilitating penile erections. It may also have a CNS neuroprotective effect.

Receptors

NO diffuses into cells and interacts directly with enzymes and iron–sulfur complexes; however, it has no specific membrane receptors.

Conditions due to Alterations in NO Activity

The best-known role of NO is in generating erections (see Chapter 16). With sexual stimulation of the penis, parasympathetic neurons produce and release NO. NO then promotes the production of cyclic guanylate cyclase monophosphate (cGMP), which dilates the vascular system and creates an erection. Sildenafil slows the metabolism of cGMP and increases blood flow in the penis, which, in turn, produces, strengthens, and prolongs erections.

Neurologic Aspects of Drug Abuse

Cocaine

Pharmacology

Cocaine and amphetamines (see later) act primarily as CNS stimulants through sympathomimetic mechanisms. Cocaine provokes a discharge of dopamine from its presynaptic storage vesicles and then blocks its reuptake. Although resulting more from blocked reuptake than forced discharge, a greatly increased dopamine synaptic concentration over-stimulates its receptors, especially those in the mesolimbic system.

Cocaine similarly blocks the reuptake of serotonin and norepinephrine. The resulting enhanced serotonin activity presumably produces euphoria. The excess norepinephrine activity causes pronounced sympathomimetic effects, such as arrhythmias, hypertension, vasospasm, and pupillary dilation. (Similarly, following instillation of 2–10% cocaine eye drops, normal pupils widely dilate because cocaine leads to local α1 stimulation.)

Cocaine also blocks nerve impulses in the PNS. Thus, when cocaine is applied or injected at a specific site, it produces local anesthesia.

Individuals who use cocaine usually smoke its solid alkaloid form (crack). Although cocaine users rarely swallow the drug, couriers (“mules”) occasionally have cocaine-filled condoms break open in their intestines, prompting a massive absorption of the drug.

Plasma and liver enzymes rapidly metabolize cocaine, giving it a half-life as brief as 30–90 minutes. Nevertheless, urine toxicology screens may detect cocaine’s metabolic products for 2 days.

Clinical Effects

The immediate effects of cocaine typically consist of a short period of intense euphoria accompanied by a sense of increased sexual, physical, and mental power. Individuals using cocaine remain fully alert – even hypervigilant. Their heightened awareness is a prominent exception to the general rule that patients in delirium or a toxic-metabolic encephalopathy are lethargic or stuporous and have a fluctuating level of consciousness (see Chapter 7). In contrast to the miosis produced by opioids, particularly heroin, cocaine users have dilated pupils.

Cocaine, like other stimulants, not only reduces sleep time, it suppresses REM sleep, often to the point of eliminating it. Another characteristic effect follows individuals’ discontinuing cocaine: They experience a rebound in REM sleep as if to compensate for the loss of REM during intoxication (see Chapter 17).

Overdose

When taking greater than their usual dose, cocaine users may become agitated, irrational, hallucinatory, and paranoid. Moreover, cocaine’s sympathomimetic and dopaminergic effects may produce permanent neurologic damage, such as strokes, myocardial infarctions, and seizures.

Cocaine-induced strokes usually occur within 2 hours of cocaine use. Although some cocaine-induced strokes are nonhemorrhagic (“bland”) cerebral infarctions, most are cerebral hemorrhages that reflect cocaine-induced hypertension or vasculitis.

Cocaine-induced seizures, which also occur within 2 hours of drug use, disproportionately follow first-time exposure. Sometimes they are the presenting sign of a cocaine-induced stroke. For practical purposes, the development of a seizure disorder in a young adult should prompt an investigation for drug abuse.

In contrast, use or even an overdose of barbiturates, benzodiazepines, or alcohol rarely causes strokes or seizures. Withdrawal from any of these substances, however, frequently precipitates not only seizures but also status epilepticus (see Chapter 10).

Probably because cocaine suddenly increases dopamine activity, its use also produces involuntary movements, such as tic-like facial muscle contractions, chorea, tremor, dystonia, and repetitive, purposeless behavior (stereotypies; see Chapter 18). Cocaine also exacerbates tics in individuals with Tourette or other tic disorder. When cocaine induces chorea, patients’ legs and feet move incessantly, and they cannot stand at attention. Neurologists label these involuntary movements “crack dancing,” and point out that they mimic chorea, restless legs syndrome, akathisia, and undertreated agitation.

In addition, cocaine seems to increase sensitivity to neuroleptic-induced dystonic reactions. For example, hospitalized cocaine users, compared to other inpatients, have a manifold increase in dystonic reactions to neuroleptics.

Studies have not established the frequency, nature, or severity of cocaine-induced cognitive impairment. However, some studies indicate that individuals repeatedly using cocaine have cognitive defects that consist of impairments in attention, verbal learning, and memory. When these deficits are present, a stroke and other brain damage are probably responsible.

Computed tomography of habitual cocaine users shows cerebral atrophy. With its superior resolution, magnetic resonance imaging also shows demyelination, hyperintensities, vasospasm, and stroke-like defects. Functional imaging, such as single photon emission computed tomography, shows multiple patchy areas of hypoperfusion (a “Swiss cheese” pattern).

Treatment of Intoxication and Overdose

Behavioral and cognitive aspects of cocaine overdose generally resolve spontaneously. Rest, seclusion, and, if necessary, benzodiazepines will moderate agitation and related symptoms. Dopamine-blocking antipsychotic agents will reduce or eliminate psychosis and violent behavior; however, because some neuroleptics, as well as cocaine itself, may lower the seizure threshold, physicians must choose and administer them judiciously. Potentially life-threatening hypertension, another hazard of cocaine, may require aggressive treatment with an α-blocker antihypertensive medication, such as phentolamine (see Table 21-2).

Withdrawal

When deprived of cocaine, habitual users often rapidly lose their energy and ability to appreciate their normally pleasurable activities, i.e., they “crash.” While typically craving the stimulation, they languish in a dysphoric mood. Vivid, disturbing dreams, which probably represent REM rebound, disturb their sleep. However, they do not suffer the physical tortures – wrenching bone pain or autonomic disturbances – that characterize withdrawal from heroin.

Reflecting the lack of dopamine receptor stimulation during withdrawal, dopamine agonists and other dopamine-enhancing medications often alleviate some withdrawal symptoms. Probably by restoring depleted serotonin stores, antidepressants may also help.

Amphetamine

The term “amphetamine” commonly refers to illicit stimulants, particularly methamphetamine (crystal, ice, speed), and stimulant medications, such as dextroamphetamine (Dexedrine) and methylphenidate (Ritalin). Like cocaine, amphetamine provokes a powerful presynaptic dopamine discharge and then blocks its reuptake. To a lesser degree, it also increases norepinephrine activity that produces sympathomimetic effects and complications, including strokes. Chronic amphetamine use may lead to long-lasting cognitive impairment and psychiatric disturbances.

When given to children and adults with attention deficit hyperactivity disorder, amphetamine paradoxically suppresses physical and mental hyperactivity. One theory suggests that amphetamine stimulates inhibitory neurons but does not affect the less sensitive, excitatory ones.

Amphetamines produce cocaine-like effects, including a hyperalert state, decreased total sleep time, and reduced proportion of REM sleep. Because the half-life of amphetamine is generally about 8 hours, its effects persist much longer than those of cocaine. Methamphetamine, which is lipophilic and therefore readily crosses the blood–brain barrier, has a half-life of 12 hours.

Overdose

As with cocaine, amphetamine overdose may cause dyskinesias, stereotypies, and thought disorders accompanied by hallucinations that can reach psychotic proportions. However, an overdose rarely causes seizures.

Because the pharmacology of amphetamine is similar to cocaine’s, treatment of amphetamine overdose also relies on dopamine-blocking neuroleptics. Likewise, symptoms of withdrawal from these substances and their treatment are similar.

Ecstasy

MDMA, best known as the stimulant ecstasy, rapidly empties presynaptic serotonin stores to create a wave of serotonin throughout the CNS. With continued use, it destroys serotoninergic neurons. Ecstasy routinely creates emotional aberrations, such as euphoria, and unexpected emotional closeness, and somatic symptoms, such as dry mouth, bruxism, and sweating. The autonomic disturbances may lead to hyperthermia, which, following compensatory water drinking, may lead to hyponatremia.

Opioids

Pharmacology

Opioid is a broad term encompassing medical narcotics, “street” narcotics, and endogenous opiate-like substances (see endorphins, Chapter 14). Although opioids may inhibit the reuptake of monamines and affect other neurotransmitters, their primary action is directly on a group of specific opioid receptors that are situated in the brain and spinal cord. Of the several opioid receptors, the mu receptors mediate opioid-induced euphoria.

Clinical Effects

Medical opioids may lessen pain, ease suffering, and reduce anxiety. Higher doses, usually associated with the early stages of abuse, lead to euphoria, a sense of well-being, and then sleepiness. Sometimes opioids paradoxically produce agitation, psychosis, and mood changes. Intravenously administered opioids routinely lead to nausea and vomiting, which presumably result from opioids directly stimulating the medulla’s chemoreceptor trigger zone. Either directly related to intravenous drug abuse or indirectly to their lifestyle, opioid abusers sometimes suffer brain damage from vasospasm, bacterial endocarditis, acquired immunodeficiency syndrome (AIDS), foreign particle emboli, and head trauma.

Overdose

Opioid overdose causes a characteristic triad of coma, miosis, and potentially fatal respiratory depression. The respiratory depression takes the form of slowed rate rather than shallower depth of breathing, which often causes neurogenic pulmonary edema. The coma routinely leads to nerve compression from prolonged, static positioning of the body (see Chapter 5). In contrast to the complications of stimulants, opioid-induced strokes or seizures rarely occur.

If an overdose leads to hypoxia, patients may suffer damage of the basal ganglia and cerebral cortex that can result in cognitive impairment. However, formal studies have failed to demonstrate cognitive impairment with chronic, well-controlled opioid use. For example, individuals on methadone maintenance programs, patients treated with opioids for chronic pain, and well-known intellectuals who abused opioids have not shown cognitive decline.

Several opioid antagonists, which displace morphine and other medicinal opioids from their receptors, reverse opioid-induced respiratory depression and other life-threatening effects. On the other hand, in the case of patients under treatment with opioids for severe pain, opioid antagonists reverse the analgesia and allow patients’ pain and agony to return. Occasionally, administering an opioid antagonist, such as naloxone (Narcan), precipitates narcotic withdrawal. Another antagonist, naltrexone (ReVia), an oral opioid maintenance or detoxification medication, also prevents opioids from reaching their receptors and thus blocks their usual effects.

Withdrawal from Chronic Use

Prominent features of opioid withdrawal typically include drug- or medication-seeking behavior, dysphoric mood, lacrimation, abdominal cramps, piloerection, and autonomic hyperactivity. Heroin withdrawal symptoms begin within several hours after the last dose and peak at 1–3 days. Because of methadone’s longer half-life, its withdrawal symptoms begin 1–2 days after the last dose and peak at about 6 days. Clonidine, the α2 norepinephrine agonist, may alleviate autonomic symptoms of opioid withdrawal.

Other Clinical Aspects

Physicians should be aware of several miscellaneous aspects of opioid use. Medical personnel, including physicians, dentists, nurses, and other health care workers, are particularly at risk for surreptitious opioid abuse. They have been prone to develop illicit dependence on readily available, highly addictive opioids, particularly meperidine (Demerol) and fentanyl (Sublimaze).

Physicians should avoid prescribing several medicines to patients enrolled in methadone maintenance programs. For example, phenytoin (Dilantin) and carbamazepine (Tegretol) enhance methadone metabolism or interfere with its receptor. When given to individuals taking daily methadone, these medicines will likely precipitate opioid withdrawal symptoms. Increasing the methadone dose when these medicines are added will greatly reduce or even prevent the problem.

Compared to morphine, heroin more easily penetrates the blood–brain barrier. Heroin does not have a specific CNS receptor, but, like morphine, it attaches to the mu receptor and produces the same effects as morphine. Contrary to some popular pronouncements, heroin holds no medically distinguishable advantage as a treatment for cancer patients.

Phencyclidine

PCP is simultaneously a central analgesic, depressant, and hallucinogen. PCP users usually snort, swallow, or smoke it, often along with marijuana or tobacco. In its primary mechanism of action, PCP blocks the NMDA receptor and prevents glutamate from interacting with it. The PCP–NMDA receptor interaction thus prevents the normal glutamate-induced influx of calcium.

In small doses, PCP use mimics alcohol intoxication in that it causes euphoria, dysarthria, ataxia, and nystagmus. At higher doses, it causes disorganized and bizarre thinking, negativism, and visual hallucinations.

Moreover, PCP may cause delusions, paranoia, and hallucinations (the positive symptoms of schizophrenia) and psychomotor retardation and emotional withdrawal (the negative symptoms). With its capacity to produce the full range of schizophrenia symptoms, PCP stands apart from LSD and other psychomimetic drugs, which usually produce only the positive symptoms. Because PCP use produces both the positive and negative symptoms, it serves as a laboratory model of schizophrenia.

Overdose

PCP overdose causes combinations of muscle rigidity, characteristic bursts of horizontal and vertical nystagmus, stereotypies, and a blank stare. PCP-induced muscle rigidity may cause rhabdomyolysis and other features of NMS, but physicians rarely confuse these two conditions. PCP-intoxicated individuals typically lie with their eyes open, unaware of their surroundings, and oblivious to pain. Neurologists describe them as being in “PCP coma.” Sometimes PCP overdose causes seizures that progress to status epilepticus; however, PCP rarely causes strokes. Another important aspect of PCP overdose is that the drug-induced psychosis often leads to violent incidents, such as motor vehicle accidents, confrontations with police, and drowning.

Multiple exposures to PCP, according to individual reports, produce chronic memory impairment and confusion. In addition, one study found that about one-fourth of individuals who experienced a PCP-induced psychosis returned in about 1 year with the diagnosis of schizophrenia.

Treatment

Unlike for opioid antagonists, no particular medicine acts as an antagonist for PCP. Treatment is symptomatic and may include seclusion and sedation with benzodiazepines. Because PCP often causes muscle rigidity, physicians should reserve antipsychotic agents, such as haloperidol, which might further increase muscle rigidity, for extreme situations. If muscle rigidity develops, muscle relaxants, such as dantrolene, may prevent rhabdomyolysis. Benzodiazepines will abort seizures.

Ketamine

Ketamine is a legitimate veterinary anesthetic. It has a chemical structure similar to PCP and also blocks NMDA receptors. Although ketamine produces many of the same mood and thought disturbances as PCP, its effects are briefer and less likely to include hallucinations, agitation, and violence.

Gamma-hydroxybutyrate

Metabolism of GABA yields, in part, gamma-hydroxybutyrate (GHB). Sodium oxybate (Xyrem), the pharmacologic preparation, is its sodium salt. These substances probably activate GABAB receptors and thereby reduce dopamine activity.

GHB has gained notoriety as the “date rape” drug or agent involved in drug-facilitated sexual assault. As an intoxicant, GHB induces an almost immediate deep sleep-like state. About 2 hours after ingestion, victims return to full consciousness with little or no recall.

Nevertheless, sodium oxybate has legitimate use in the treatment of narcolepsy with cataplexy (see Chapter 17), where it has approved indications for treatment of cataplexy and excessive daytime sleepiness. Its benefits likely stem, in large part, from its ability to increase restful slow-wave sleep. Physicians and pharmacies must monitor prescriptions and distribution for sodium oxybate because of its potential nefarious use.

Marijuana

Marijuana (cannabis) is a cannabinoid that contains several psychoactive ingredients, but the most potent is Δ9-THC. The cerebral cortex, basal ganglia, hippocampus, and cerebellum all contain specific Δ9-THC receptors.

In mild, recreational doses, marijuana produces euphoria and pleasantly altered perceptions, but it slows thinking and impairs judgment. Its effects usually last 1–3 hours, but heavy use can result in symptoms that last 1–2 days. As with other illicit drugs, marijuana reduces REM sleep.

Overdose

Unlike sedative effects of small doses of marijuana, a large dose can paradoxically cause pronounced anxiety or psychosis. If these symptoms do not spontaneously recede, benzodiazepines or, if necessary, antipsychotic agents – as well as the passage of time – can control them. In contrast to overdoses of other drugs of abuse, marijuana overdoses are not fatal. Moreover, marijuana overdoses rarely, if ever, cause acute neurologic problems, such as seizures or strokes.

Other Considerations

Marijuana possesses several undeniable beneficial pharmacologic properties that serve as the springboard in attempts to legalize it. For example, marijuana purportedly possesses anticonvulsant activity, reduces intraocular pressure, reduces chemotherapy-induced nausea and vomiting, and provides analgesia for multiple sclerosis-induced pain and spasticity.

On the other hand, advocates overstate its medicinal benefits. Conventional medicines are more effective for each of these purposes. For example, D2 dopamine and 5-HT3 serotonin antagonists are much more effective than marijuana as antiemetics. Also, although marijuana lowers intraocular pressure, its effect is too mild and short-lived to constitute a useful treatment for glaucoma patients. In multiple sclerosis, the prolonged use of the drug impairs cognition to a much greater degree than it relieves pain and physical symptoms.

Moreover, marijuana carries a risk of deleterious effects. It is associated with motor vehicle accidents. Also, drug enforcement agencies, attempting to kill marijuana plants, spray them with toxic chemicals (herbicides). Those herbicides remain on the leaves of surviving plants and smokers inhale their residue.

Although acute marijuana-induced cognitive impairments are mild and transient with occasional use, chronic heavy use causes dose-related impairments in executive function, psychomotor speed, and especially memory. Heavy marijuana use among adolescents is more deleterious than among adults. It also probably induces cerebral atrophy. On the other hand, studies have been unable to prove that chronic marijuana use causes dementia.

Nicotine

Nicotine binds to mesolimbic nicotinic cholinergic receptors. In addition, as with other drugs of abuse, nicotine provokes the release of dopamine in the mesolimbic system and frontal cortex to provide pleasure, enhance mood, and reduce anxiety. Almost all individuals who use nicotine obtain it from cigarettes, which, as the tobacco industry has acknowledged, serve primarily as nicotine delivery devices. The main impetus for chronic cigarette use ironically lies more in suppressing withdrawal symptoms – anxiety, restlessness, tremulousness, and craving – than deriving pleasure or reducing anxiety. Nicotine in cigarettes has no appreciable cognitive effect, but individuals going through withdrawal may have temporary impairment because of anxiety, poor concentration, and preoccupation with their lack of cigarettes.

Although stopping tobacco use is usually voluntary, it is often coerced, involuntary, and unexpected, as when smokers are hospitalized. Varenicline (Chantix), a tobacco cessation medicine, is a partial agonist of certain nicotinic ACh receptors. Another antitobacco product, bupropion (Zyban and Wellbutrin) is a nicotine receptor antagonist and an inhibitor of dopamine reuptake. It increases dopamine concentration in the mesolimbic system. Unfortunately, even under the protection of varenicline or bupropion, tobacco withdrawal may lead to depressed mood, agitation, suicidality, and worsening of pre-existing psychiatric illness.

“Bath Salts”

Clearly not a bathing or beauty product, “bath salts” or “psychoactive bath salts” are a group of stimulants with benign names, such as Ivory Wave and White Horse. Their active ingredient, methylenedioxyprovalerone, inhibits dopamine and norepinephrine reuptake. Thus, they cause cocaine-like effects: agitated delirium, often with paranoid aspects and hallucinations, and sympathetic overstimulation with tachycardia, hypertension, and enlarged pupils. They also cause cocaine-like vascular complications: stroke and myocardial infarction.

Change in mental status or dangerous behavior may require small doses of antipsychotic agents. Sympathetic overstimulation may require intravenous benzodiazepine.

References

Neurotransmitters

Benarroch EE. GABAB receptors. Neurology. 2012;78:578–584.

Hilker R, Thomas AV, Klein JC, et al. Dementia in Parkinson’s disease: Functional imaging of cholinergic and dopaminergic pathways. Neurology. 2005;65:1716–1722.

Hshieh TT, Fong TG, Marcantonio ER, et al. Cholinergic deficiency hypothesis in delirium: A synthesis of current evidence. J Gerontol. 2008;63A:764–772.

McKeon A, Robinson MT, McEvoy KM, et al. Stiff-man syndrome and variants: Clinical course, treatments, and outcomes. Arch Neurol. 2012;69:230–238.

Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 3rd ed. Cambridge: Cambridge University Press; 2008.

Drug Abuse

Baylen CA, Rosenberg H. A review of the acute subjective effects of MDMA/ecstasy. Addiction. 2006;101:933–947.

Benowitz NL. Nicotine addiction. N Engl J Med. 2010;362:2295–2303.

Derlet RW, Rice P, Horowitz BZ, et al. Amphetamine toxicity: Experience with 127 cases. J Emerg Med. 1989;7:157–161.

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Hays JT, Ebbert JO. Varenicline for tobacco dependence. N Engl J Med. 2008;359:2018–2024.

Herning RI, Better W, Tate K, et al. Neuropsychiatric alterations in MDMA users. Ann NY Acad Sci. 2005;1053:20–27.

Honarmand K, Tierney MC, O’Connor, et al. Effects of cannabis on cognitive function in patients with multiple sclerosis. Neurology. 2011;76:1153–1160.

McCarron MM, Schulze BW, Thompson GA, et al. Acute phencyclidine intoxication: Incidence of clinical findings in 1,000 cases. Ann Emerg Med. 1981;10:237–242.

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Chapter 21 Questions and Answers

1. Which are four effects of opioids?

a. Block reuptake of dopamine into presynaptic neurons
b. Cause vomiting
c. Induce hypertension
d. Decrease the rate but not the depth of respirations
e. Stimulate the area postrema
f. Cause miosis
g. Decrease the depth but not the rate of respirations

Answers:

b, d, e, f. Opioids readily strike the area postrema, which occupies a position on the dorsal surface of the medulla and contains the chemoreceptor trigger zone. The area postrema is one of the few regions of the brain unprotected by the blood–brain barrier. Intravenous injections of heroin or morphine characteristically lead to vomiting because these substances stimulate the unprotected area postrema. When opioids strike the adjacent respiratory area, which is similarly unprotected, they depress the rate but not the depth of respirations. Opioid-induced respiratory depression frequently leads to anoxia and pulmonary edema.

2. Which three features frequently complicate opioid overdose?

a. Cerebral hemorrhage
b. Respiratory arrest
c. Seizures
d. Radial nerve palsy
e. Tics
f. Stereotypies
g. Psychotic thinking
h. Pulmonary edema

Answer:

b, d, h. Opioid overdose depresses the level of consciousness and respirations, and produces other pulmonary changes that lead to pulmonary edema. Lying for prolonged periods against the upper arm frequently compresses the radial nerve, which may result in a “wrist drop.” Taking opioids and becoming stuporous, while sitting on a toilet seat, leads to compression of both sciatic nerves and a resultant bilateral foot drop. Neurologists call loss of foot and ankle strength, when it develops in this fashion, a “toilet seat neuropathy.”

3. Which three causes of seizures are disproportionately more common in 15–50-year-old individuals than in older adults?

a. Marijuana use
b. Head trauma
c. Crack cocaine use
d. Sleep deprivation
e. Brain tumors
f. Strokes

Answer:

b, c, d. Although young adults more frequently than older ones use marijuana, it is not associated with seizures. On the other hand, crack cocaine use routinely causes both strokes and seizures.

4. Which substance’s primary active ingredient is Δ9-THC?

a. Cocaine
b. Phencyclidine (PCP)
c. Amphetamine
d. Cannabis
e. Heroin

Answer:

d. Cannabis is marijuana, and its primary active ingredient is Δ9-THC.

5. When the patient develops unilateral miosis, ptosis, and anhidrosis, which neurotransmitter is most likely deficient?

a. Acetylcholine (ACh)
b. Dopamine
c. Norepinephrine
d. Serotonin

Answer:

c. The patient has Horner syndrome, which results from sympathetic nerve damage in the ciliary ganglion. Thus, it is a manifestation of norepinephrine deficiency.

6. A former heroin addict has a history of epilepsy as a teenager. While attending his methadone maintenance program, he developed a flurry of seizures. Emergency room physicians responded and administered phenytoin (Dilantin). Although it controlled the seizures, the patient became agitated and combative. He also reported nausea and abdominal pain. A psychiatrist found piloerection and muscle cramps. Clinical chemistry, urine analysis, and hematology laboratory results were normal except for the presence of opiates or their metabolic products in the urine. Which is the best course of action?

a. Insist on computed tomography (CT) and electroencephalography (EEG) before treating.
b. Administer naloxone (Narcan).
c. Increase the dose of phenytoin.
d. Increase the dose of methadone.

Answer:

d. Phenytoin increases the metabolism of methadone. When physicians administer it to individuals in methadone maintenance programs, the interaction may be so powerful that the patient goes into withdrawal – as in this case. Another cause of withdrawal occurs when physicians prescribe inadequate doses of methadone to addicts when they are hospitalized or incarcerated. In both scenarios, raising the dose of methadone will alleviate the symptoms.

7. Which is the primary mechanism of action of acute cocaine intoxication?

a. It enhances dopamine activity.
b. It enhances serotonin metabolism.
c. It reduces serotonin metabolism.
d. It reduces gamma-aminobutyric acid (GABA) levels.

Answer:

a. Cocaine suddenly increases dopamine activity by triggering its release from presynaptic nerve endings and then blocking its reuptake.

8. Which is not a sign of excessive sympathetic activity?

a. Tachycardia
b. Eyelid retraction
c. Hypertension
d. Miosis

Answer:

d. With excessive sympathetic activity, pupils dilate.

9. Which one of the following is not a manifestation of amphetamine use?

a. Weight loss
b. Stereotypies
c. Psychosis similar to cocaine-induced psychosis
d. Parkinsonism

Answer:

d. Use of synthetic opioids contaminated by MPTP, which destroys nigrostriatal neurons, is a classic cause of parkinsonism. Amphetamines cause the other symptoms.

10. The police bring a comatose young man to the emergency room. He has a weak and thready pulse, infrequent and shallow respirations, and miosis. A chest X-ray shows pulmonary edema. After securing an airway, which should be the medical staff’s next treatment?

a. Naloxone
b. Thiamine
c. Haloperidol
d. Glucose

Answer:

a. He probably has a heroin or other opioid overdose, which classically causes coma, miosis, respiratory depression, and pulmonary edema. Naloxone, a narcotic antagonist, reverses opioid overdose. Because the half-life of naloxone is relatively short, patients with heroin or methadone overdose often require repeated naloxone administration.

11. Which substance has the weakest antiemetic effect?

a. Marijuana
b. D2 dopamine blockers
c. 5HT3 antagonists

Answer:

a. D2 dopamine blockers and 5HT3 antagonists have substantial antiemetic effects. Marijuana has relatively weak antiemetic effects, which do not justify its popular support as a chemotherapy adjunct.

12. Which antipsychotic characteristic is associated with the fewest extrapyramidal effects?

a. Potent nicotinic antagonist effects
b. Potent dopaminergic antagonist effects
c. Potent muscarinic antagonist effects
d. Potent dopaminergic agonist effect

Answer:

c. Antipsychotics that have potent muscarinic antagonist effects, such as clozapine and olanzapine, produce fewer extrapyramidal side effects.

13. Which product of dopamine metabolism is measurable in the cerebrospinal fluid (CSF)?

a. Monoamine oxidase (MAO)
b. Homovanillic acid (HVA)
c. Catechol-O-methyltransferase (COMT)
d. Vanillylmandelic acid (VMA)

Answer:

b. MAO and COMT are metabolic enzymes that act on dopamine. VMA, which is excreted in the urine, is a metabolic product of norepinephrine.

14. Which is the rate-limiting enzyme in the synthesis of dopamine?

a. DOPA decarboxylase
b. Tyrosine hydroxylase
c. MAO
d. COMT
e. Dopamine β-hydroxylase

Answer:

b.

15. Of the enzymes listed in Question 14, which converts dopamine to norepinephrine?

Answer:

e.

16. Of the choices listed in Question 14, which is the rate-limiting enzyme in the synthesis of norepinephrine?

Answer:

b. As a general rule, tyrosine hydroxylase is the rate-limiting enzyme in catecholamine synthesis.

17. Which two statements about stimulating D1 and D2 dopamine receptors are correct?

a. Stimulation of the D1 receptor increases cyclic AMP activity.
b. Stimulation of the D2 receptor decreases cyclic AMP activity.
c. Stimulation of the D1 receptor decreases ATP to cyclic AMP production.
d. Stimulation of the D2 receptor increases ATP to cyclic AMP production.

Answer:

a, b.

18. Which dopamine tract is responsible for the elevated prolactin concentration induced by many antipsychotic agents?

a. Nigrostriatal
b. Mesolimbic
c. Tubero-infundibular
d. None of the above

Answer:

c. The tubero-infundibular tract connects the hypothalamus and the pituitary gland. Dopamine D2 blockade provokes prolactin release and elevates serum prolactin concentration. By way of contrast, dopamine blockade of the mesolimbic system correlates with these medicines’ antipsychotic effect.

19. Which is the primary site for conversion of norepinephrine to epinephrine?

a. Locus ceruleus
b. Striatum
c. Adrenal medulla
d. Nigrostriatal tact

Answer:

c.

20. Which is the major metabolic pathway for serotonin?

a. Metabolism by COMT to 5-hydroxyindoleacetic acid (5-HIAA)
b. Metabolism by MAO to 5-HIAA
c. Metabolism by decarboxylase to HVA
d. Metabolism by HVA to 5-HIAA

Answer:

b. Although serotonin, like dopamine, mostly undergoes reuptake, MAO metabolizes the remainder of serotonin to 5-HIAA.

21. Where is the main site of serotonin production?

a. Dorsal raphe nuclei
b. Regions adjacent to the aqueduct in the midbrain
c. Striatum
d. None of the above

Answer:

d. Almost all serotonin is produced in platelets, the gastrointestinal tract, and other nonneurologic organs. However, within the brain, serotonin-producing neurons are located predominantly in the dorsal raphe nuclei, which are near the aqueduct in the dorsal midbrain. Although plentiful, these neurons produce only 2% of the body’s total serotonin.

22. A 48-year-old man, with a history of major depression, commits suicide by igniting several sticks of dynamite. Which neurotransmitter abnormality would investigators most likely find on postmortem examination?

a. Low concentrations of CSF HVA
b. Low concentrations of CSF HIAA
c. Low GABA concentrations in the basal ganglia
d. High dopamine concentrations

Answer:

b. Low concentration of CSF HIAA characterizes violent suicides. The low concentration of CSF HIAA reflects decreased central nervous system (CNS) serotonin activity. Low GABA concentrations in the basal ganglia are characteristic of Huntington disease.

23. Which statement is false regarding ACh receptors in the cerebral cortex?

a. They are predominantly muscarinic.
b. They are predominantly nicotinic.
c. Atropine blocks muscarinic receptors.
d. Scopolamine, which antagonizes muscarinic receptors, induces memory impairments that mimic Alzheimer disease dementia.

Answer:

b. Cerebral cortex ACh receptors are predominantly muscarinic. Blocking CNS muscarinic receptors, with scopolamine for example, causes memory impairments even in normal individuals.

24. In the synthesis of ACh from acetyl-coenzyme A and choline, which is the rate-limiting factor?

a. Choline acetyltransferase
b. Acetyl coenzyme A
c. Choline
d. None of the above

Answer:

c.

25. Which two comparisons of Lambert–Eaton syndrome and myasthenia gravis are true?

a. Lambert–Eaton syndrome is a paraneoplastic syndrome, whereas myasthenia gravis is an autoimmune disorder.
b. Lambert–Eaton syndrome is associated with decreased ACh production, whereas myasthenia gravis is associated with excess ACh production.
c. Lambert–Eaton syndrome is characterized by impaired presynaptic ACh release, whereas myasthenia gravis is characterized by defective ACh receptors.
d. Lambert–Eaton syndrome is alleviated by botulism, whereas myasthenia gravis is alleviated by anticholinesterases (cholinesterase inhibitors).

Answer:

a, c. In both illnesses, impaired ACh activity at the neuromuscular junction causes muscle weakness. Impaired presynaptic ACh release characterizes Lambert–Eaton syndrome. Although usually a paraneoplastic syndrome, Lambert–Eaton may represent a purely autoimmune disorder. In contrast, myasthenia gravis is an autoimmune disorder characterized by defective ACh receptors on the postsynaptic membrane.

26. When GABA interacts with postsynaptic GABAA receptors, which four events are likely to occur?

a. Sodium channels are opened.
b. Chloride channels are opened.
c. The electrolyte shift depolarizes the neuron.
d. The electrolyte shift hyperpolarizes the neuron.
e. Hyperpolarization leads to inhibition.
f. The electrolyte shift in polarization leads to excitation.
g. Glutamate provokes a similar response.
h. Glycine provokes a similar response.

Answer:

b, d, e, h. The GABAA receptor is ubiquitous, multifaceted, and sensitive to benzodiazepines and barbiturates as well as GABA. When stimulated, the GABAA receptor permits the influx of chloride. The electrolyte shift hyperpolarizes the neuron’s membrane and inhibits depolarization. Glycine, like GABA, is an inhibitory amino acid neurotransmitter.

27. Which is the approximate normal resting potential of neurons?

a. +100 mV
b. +70 mV
c. 0 mV
d. –70 mV
e. –100 mV

Answer:

d. The normal resting potential is –70 mV. When the resting potential is –100 mV, the neuron is hyperpolarized and thereby inhibited.

28. Which two roles do glycine play?

a. Glycine is an inhibitory amino acid neurotransmitter.
b. Glycine modulates the N-methyl-D-aspartate (NMDA) receptor.
c. Glycine is the rate-limiting substrate in glutamate synthesis.
d. Glycine raises the resting potential (i.e., makes it less negative).

Answer:

a, b. Glycine is primarily an inhibitory amino acid neurotransmitter but it also modulates the NMDA receptor. Inhibitory neurotransmitters generally make the resting potential more negative.

29. Of the following, by which two methods does the nervous system deactivate dopamine?

a. Decarboxylation
b. Oxidation
c. Reuptake
d. Hydroxylation

Answer:

b, c. Most dopamine undergoes reuptake, but MAO and COMT metabolize the remainder.

30. Which neurotransmitter is confined almost entirely to the brain?

a. Dopamine
b. Glutamate
c. Glycine
d. Norepinephrine
e. Serotonin

Answer:

a. Dopamine is found in the adrenal medulla, but its primary tracts are confined to the brain. The other neurotransmitters may be found in the spinal cord or autonomic nervous system, as well as the brain.

31. Which are two effects of glutamate–NMDA interaction?

a. Intracellular neuron calcium concentration increases.
b. Inhibition occurs through hyperpolarization.
c. Excitation occurs under normal circumstances.
d. Excitotoxicity occurs under normal circumstances.
e. Inhibition occurs under normal circumstances.

Answer:

a, c. Glutamate, the principal CNS excitatory neurotransmitter, interacts with the NMDA and other receptors to open calcium channels. With excessive activity, excitotoxicity, the calcium influx raises intracellular concentrations to lethal levels.

32. Of the following, which is the best treatment for atropine poisoning?

a. Scopolamine
b. Edrophonium
c. Neostigmine
d. Physostigmine

Answer:

d. Atropine is an inhibitor of muscarinic cholinergic receptors. Physostigmine, an anticholinesterase, crosses the blood–brain barrier and elevates ACh concentration.

33. In Alzheimer disease, which of the following receptors is most depleted?

a. Muscarinic ACh
b. Nicotinic ACh
c. Nigrostriatal dopamine
d. Frontal dopamine

Answer:

a. In Alzheimer disease, muscarinic ACh receptors are severely depleted, especially in the limbic system and association areas.

34. Which one of the following inhibits dopamine metabolism and yields amphetamine-like metabolites?

a. Haloperidol
b. Selegiline (deprenyl)
c. Amitriptyline

Answer:

b. Although the neuroprotective role of selegiline remains unproven, it inhibits dopamine metabolism and improves parkinsonism. Selegiline also provides an antidepressant effect partly through its metabolic products, amphetamine and methamphetamine.

35. What effect does tetrabenazine have on dopamine transmission?

a. It stimulates dopamine transmission by acting as a precursor.
b. It substitutes for dopamine by acting as an agonist.
c. It interferes with dopamine transmission by blocking D2 receptors.
d. It reduces dopamine transmission by depleting dopamine from its presynaptic storage sites.

Answer:

d. Tetrabenazine depletes dopamine from its presynaptic storage sites and thereby reduces involuntary movements. Tetrabenazine is useful in the treatment of hyperkinetic movement disorders, such as chorea, Tourette syndrome, and oral-bucco-lingual tardive dyskinesia. Unfortunately, tetrabenazine-induced dopamine reduction may lead to parkinsonism and depression with suicide ideation. It also leads to an innocuous elevation of serum prolactin.

36. A 50-year-old man is hospitalized for alcohol withdrawal. His physicians prophylactically order clonidine and a β-blocker. Which of the following complications will not be prevented by this treatment?

a. Tachycardia
b. Tremor
c. Agitation
d. Seizures
e. Hypertension

Answer:

d. During alcohol withdrawal, these medicines will reduce cardiovascular and some psychological manifestations; however, they will not prevent alcohol withdrawal seizures. Clonidine, an α2 norepinephrine agonist, may alleviate autonomic symptoms of opioid withdrawal, but will not prevent the seizures.

37. A neurologist admitted a 23-year-old woman with 1 week of progressively severe delirium. Then she developed myoclonus and finally a flurry of seizures. An exhaustive evaluation found only that her serum contained antibodies to the NMDA receptor. Which is the most likely underlying pathology?

a. Huntington disease
b. PCP intoxication
c. Ovarian teratoma
d. Memantine (Namenda) intoxication

Answer:

c. In a paraneoplastic syndrome, particularly the one triggered by ovarian teratomas in young women, antibodies directed toward NMDA receptors create an autoimmune limbic encephalitis. PCP and ketamine may block the NMDA calcium channel and cause psychosis. Memantine, an NMDA receptor antagonist, blocks its deleterious excitatory neurotransmission.

38. Which one of the following characterizes fast neurotransmitters?

a. They work through ion channels.
b. They work through G proteins.
c. They work through second messengers.
d. They include dopamine and norepinephrine.

Answer:

a. Fast neurotransmitters, such as GABA and glutamate, work through ion channels. Slow neurotransmitters, such as the catecholamines, work through G proteins and second messengers, such as adenyl cyclase.

39. To which process do excessive glutamate–NMDA interactions lead?

a. Hyperpolarization
b. Excitotoxicity
c. Apoptosis
d. Involution

Answer:

b. Excessive NMDA activation – excitotoxicity – leads to flooding of the neurons with lethal concentrations of calcium.

40. Which of the following statements is false regarding serotonin?

a. Serotonin is a monoamine, but not a catecholamine.
b. Depending on the receptor class, serotonin interactions may lead to increased adenyl cyclase activity.
c. Serotonin is a slow neurotransmitter that works through G proteins and second messengers.
d. The antimigraine medications, triptans, are 5-HT1D receptors antagonists.

Answer:

d. In one of neurology’s most effective therapies, sumatriptan and other triptans, which are 5-HT1D receptor agonists, consistently abort migraines. Serotonin is not a catecholamine but a monoamine. It works through G proteins and second messengers.

41. Which one of the following statements concerning neurotransmission is false?

a. Glutamate–NMDA interactions are fast and excitatory.
b. Glutamate–NMDA interactions affect the calcium channel.
c. Benzodiazepine–GABAA receptor interactions are fast and inhibitory.
d. Benzodiazepine–GABAA receptor interactions affect the chloride channel.
e. Benzodiazepine–GABAA receptor interactions, which promote the influx of chloride, reduce the polarization of the resting potential.

Answer:

e. Benzodiazepine–GABAA receptor interactions promote the influx of chloride, which makes the resting potential more negative. Hyperpolarized neurons are refractory to stimulation (inhibited).

42. Which of the following is a second messenger?

a. Cyclic AMP
b. Serotonin
c. Endorphins
d. Thyroid hormone
e. Glutamate

Answer:

a. Cyclic AMP, like phosphatidyl inositol, is a second messenger.

43. Which dopamine tract is most likely responsible for positive symptoms in psychosis?

a. Nigrostriatal
b. Mesolimbic
c. Tubero-infundibular
d. Mesocortical

Answer:

b.

44. Which dopamine tract is most likely responsible for negative symptoms in psychosis?

a. Nigrostriatal
b. Mesolimbic
c. Tubero-infundibular
d. Mesocortical

Answer:

d.

45. Which of the following pairs are inhibitory amino acid neurotransmitters?

a. GABA and glycine
b. Glutamate and aspartate
c. Epinephrine and norepinephrine
d. L-dopa (levodopa) and carbidopa

Answer:

a. GABA and glycine are inhibitory amino acid neurotransmitters. Glutamate and aspartate are excitatory amino acid neurotransmitters.

46–51.Match the medication (46–51) with the enzyme (a–e) that it inhibits.

46. Selegiline

47. Carbidopa

48. Entacapone

49. Edrophonium

50. Tranylcypromine

51. Pyridostigmine

a. Dopa decarboxylase
b. COMT
c. MAO-B
d. Acetylcholinesterase
e. MAO-A

Answers:

46-c; 47-a; 48-b; 49-d; 50-e; 51-d.

52–56.Match the illness (52–56) with the deficient enzyme(s) (a–d). More than one answer may be appropriate.

52. Phenylketonuria

53. Parkinson disease

54. Dopamine-responsive dystonia

55. Alzheimer disease

56. Huntington disease

a. Phenylalanine hydroxylase
b. Tyrosine hydroxylase
c. Glutamate decarboxylase
d. Choline acetyltransferase

Answers:

52-a; 53-b; 54-a and b; 55-d; 56-c.

57. Recalling that the neurologist explained that antiparkinson medicines cause nocturnal hallucinations, a patient’s family suddenly discontinued all his Parkinson disease medicines because he had developed severe nocturnal visual hallucinations. Rigidity returned on the first day. On the next day, when he became “stiff as a board,” febrile, and delirious, his family brought him to the emergency room. The medical staff found him stuporous, febrile, and rigid. While awaiting blood test results, which treatments should the staff administer in addition to providing supportive therapy, e.g., fluids, glucose, and electrolytes?

a. A second-generation antipsychotic
b. Dantrolene and his usual Parkinson disease medicines
c. Aspirin
d. A first-generation antipsychotic

Answer:

b. Most likely the patient has developed the neuroleptic-malignant syndrome (dopamine depletion syndrome) because the family abruptly stopped his Parkinson disease medications. An infection may be the cause of his delirium and fever, but probably not the rigidity. The medical staff should administer dantrolene and reinstitute his usual Parkinson disease medicines to prevent rhabdomyolysis and renal failure. Using an antipsychotic agent in this setting is problematic. A benzodiazepine might reduce his agitation, give him some rest, and allow him to cooperate with his treatment.

58. The police bring a young man to the psychiatric emergency room after he wandered through the streets saying that he took some medicine from a friend. He appears anxious, but he repeats that he feels “close to everyone.” His pupils have a normal diameter and reactivity to light. His eyes have full, conjugate movement without nystagmus. He grinds his teeth. Which is the most likely intoxicant?

a. A dopamine-blocking antipsychotic agent
b. PCP
c. Heroin
d. Ecstasy

Answer:

d. Ecstasy intoxication typically induces a sense of empathy but paradoxically, in many cases, anxiety. It is a stimulant that routinely causes bruxism (teeth grinding). Dopamine-blocking antipsychotic agents often cause dystonic jaw movements accompanied by oculogyric crisis. PCP causes generalized rigidity and nystagmus that is characteristically in three directions. Heroin causes miosis and placidity rather than excitement or anxiety. Compared to the change in mental status, a patient’s physical signs are often more diagnostic of the intoxicant.

59. Of the following atypical antipsychotics, which raises the serum prolactin concentration to its highest level?

a. Aripiprazole
b. Ziprasidone
c. Risperidone
d. Clozapine
e. Olanzapine

Answer:

c. Of those agents, risperidone raises the prolactin level the highest and is also the most likely to cause galactorrhea. Clozapine usually raises the prolactin level the least.

60. Which of the following is false regarding the GABAB receptor?

a. GABAB receptors are more numerous and more widely distributed than GABAA receptors.
b. GABAB receptors are G protein-linked channel inhibitors.
c. Baclofen binds to GABAB receptors.
d. Like GABAA receptors, GABAB receptors are complex molecules.

Answer:

a. GABAA receptors are more numerous and more widely distributed than GABAB receptors.

61. In a suicide attempt, a 40-year-old man, who had been under treatment for tuberculosis and major depression for several years, took an overdose of isoniazid (INH). Shortly afterwards, he developed status epilepticus. Which would be the most specific, effective treatment?

a. Topiramate
b. Thiamine
c. Lorazepam
d. Pyridoxine (B6)

Answer:

d. INH interferes with pyridoxine, which is the cofactor for glutamate decarboxylase. Glutamate decarboxylase is a crucial enzyme in GABA synthesis. Thus, large doses of INH create a GABA deficiency, and the loss of this inhibitory neurotransmitter causes seizures. In another example of pyridoxine deficiency leading to seizures, infants inadvertently fed pyridoxine-deficient diets may develop seizures. Intravenous pyridoxine aborts pyridoxine deficiency-induced seizures. Doctors prescribing INH should combine it with pyridoxine. Topiramate enhances GABAA receptor activity, but it is ineffective without GABA.

62. Which of the following statements concerning “bath salts” is true?

a. They block the reuptake of dopamine and norepinephrine.
b. They lead to a surge of parasympathetic activity.
c. They act like opioids and induce a sense of calm but also depress respirations.
d. They are naturally occurring psychoactive drugs found in Baden Baden and Wiesbaden.

Answer:

a. Methylenedioxypyrovalerone (MDPV) is the active ingredient of a new group of synthetic psychoactive drugs, “bath salts,” that block the reuptake of dopamine and norepinephrine. These stimulants, likened to synthetic cocaine, induce hallucinatory delirium and a sympathetic surge.

63. A 55-year-old bartender, who stated that he has smoked two packs of cigarettes each day but denied ever drinking alcohol, developed chronic obstructive lung disease and pneumonia for which his physician hospitalized him. After the pneumonia began to respond to treatment and his blood gas results started to return toward normal, he became cantankerous, then agitated, and sullen. When he demanded to be released, his intern called for neurology and psychiatry consultations. They determined that his physical neurologic examination, routine blood tests, and head CT were all normal. The patient insisted on a cigarette, but the medical staff would not allow him to smoke in his area of the hospital and they could not move him to a suitable location. Which would be the first, best treatment?

a. Varenicline (Chantix)
b. Bupropion
c. Alprazolam
d. Ethanol

Answer:

a. The patient is going through nicotine withdrawal. In extreme cases, alprazolam may be necessary on a temporary basis to reduce physical and mental agitation. However, varenicline, a nicotine ACh receptor agonist, would be the treatment in most cases. Alternatively the patient may benefit from bupropion, a nicotine antagonist and inhibitor of dopamine reuptake.

64. A 67-year-old woman, a recent immigrant from Central America, received fluvoxamine for depression. After drinking tea made from various herbs sold in the neighborhood botanica, she developed anxiety and tremulousness. Which medication should emergency room psychiatrists administer?

a. A benzodiazepine
b. Physostigmine
c. An atypical neuroleptic
d. None of the above

Answer:

d. The woman is experiencing a mild serotonin syndrome. The physicians should keep her calm and hydrated, and allow it to pass. In Latino communities, botanicas sell, among other products, religious icons and folk medicines, including herbs. Some folk medicine preparations contain St. John’s wort (Hypericum perforatum, a genus of flowering plants), mercury, and other potentially harmful substances. Although St. John’s wort has antidepressant properties, when taken with SSRIs, the combination may lead to the serotonin syndrome.

65. Which of the following would most likely reduce hyperkinetic involuntary movements?

a. Tetrabenazine
b. Levodopa
c. Benzodiazepine
d. Carbidopa

Answer:

a. Tetrabenazine, which depletes dopamine from presynaptic nerves in the nigrostriatal tract, reduces chorea, tics, and medication-induced dyskinesias.

66. On which receptors do second-generation antipsychotics act?

a. D1 and 5HT2A receptors
b. D2 and 5HT2A receptors
c. D2 and 5-HT1D receptors
d. D2 and 5HT3 receptors

Answer:

b. Second-generation antipsychotics act as antagonists of 5HT2A as well as D2 receptors. Triptans, the migraine medication, are selective 5-HT1D receptor agonists. Dolasetron and ondansetron, which are antiemetics used conjointly with chemotherapy agents, are 5HT3 antagonists.

67. Which drug of abuse most increases serotonin activity?

a. PCP
b. Amphetamine
c. LSD
d. Ecstasy
e. Cocaine

Answer:

d. Ecstasy greatly increases CNS serotonin activity by forcefully disgorging it from its presynaptic storage vesicles. LSD stimulates serotonin receptors, and its effects are less pronounced than those of ecstasy. Amphetamine and cocaine act on the dopamine system. PCP acts on the NMDA receptors.

68–73. Match the site of neurotransmitter synthesis (68–73) with the region(s) of the nervous system (a–e) where it is located. More than one answer may be appropriate.

68. Locus ceruleus

69. Dorsal raphe nuclei

70. Adrenal medulla

71. Substantia nigra

72. Nucleus basalis of Meynert

73. Caudal raphe nuclei

a. Basal forebrain bundle
b. Midbrain
c. Pons
d. Medulla
e. Adrenal gland

Answers:

68-c; 69-b and c; 70-e; 71-b; 72-a; 73-c and d.

74. A woman, 5 months pregnant, asks for methadone maintenance because federal agents have interrupted her heroin supply. Which action would best preserve the health of the patient and the fetus?

a. Do not accept her into a methadone maintenance program until after she delivers.
b. Have her undergo heroin detoxification to avoid exposing the fetus to methadone.
c. Enroll her in a methadone maintenance program as soon as possible.
d. None of the above.

Answer:

c. The fetus, as well as the mother, is probably addicted to heroin. Attempting to stop the mother’s opioid use abruptly would probably be futile, but physicians could probably switch her from heroin to methadone. After she delivers, physicians can detoxify both the mother and infant.

75. To which receptors do ketamine and PCP bind?

a. Dopamine
b. Norepinephrine
c. Serotonin
d. GABAA
e. NMDA

Answer:

e. Ketamine and PCP affect the ion channels of NMDA receptors.

76. What is the effect of ketamine and PCP binding on the NMDA receptor?

a. Inhibition of the influx of calcium
b. Promotion of the influx of calcium
c. Inhibition of the influx of chloride
d. Promotion of the influx of chloride
e. None of the above

Answer:

a. Ketamine and PCP inhibit the influx of calcium, which is usually provoked by interactions of glutamate or aspartate with the NMDA receptor.

77. Which of the following statements concerning sodium oxybate (Xyrem) is false?

a. It is indicated for the treatment of cataplexy in narcolepsy.
b. It is indicated for the treatment of excessive daytime sleepiness in narcolepsy.
c. It is the sodium salt of gamma-hydroxybutyrate (GHB).
d. Because it has been implicated as the agent in drug-facilitated sexual assault (“date rape”), the manufacture and sale of sodium oxybate are illegal.

Answer:

d. Sodium oxybate is indicated for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy. Because it has been implicated in drug-facilitated sexual assaults, its manufacture and sale must be closely monitored.

78. Of the following dopamine receptors, which is most stimulated by cocaine?

a. D1
b. D2 mesocortical
c. D2 mesolimbic
d. D3

Answer:

c. Cocaine mostly affects the D2 mesolimbic receptors.

79. Which is the best treatment for cocaine-induced psychosis and violent behavior?

a. Dopamine-blocking neuroleptics
b. Benzodiazepines
c. Seclusion and, if necessary, restraints
d. None of the above

Answer:

a. Because the main effect of cocaine is to increase dopamine activity by blocking its reuptake, dopamine-blocking neuroleptics are the best short-term treatment. However, in this situation, physicians should cautiously use these neuroleptics because some of them lowers the seizure threshold.

80. Which are the least common neurologic complications of cocaine use?

a. Nonhemorrhagic strokes
b. Hemorrhagic strokes
c. Seizures during withdrawal
d. Seizures during overdose
e. Increased incidence of neuroleptic-induced dystonic reactions

Answer:

c. Seizures are apt to complicate withdrawal from alcohol, barbiturates, and benzodiazepines. With cocaine, seizures complicate withdrawal only from chronic, frequent, high-dose use. However, seizures are a common complication of cocaine intoxication and may reflect a cocaine-induced stroke. Hemorrhagic and nonhemorrhagic strokes complicate cocaine use.

81. Which is the best treatment for cocaine-induced severe hypertension?

a. Diuretics
b. Calcium channel blockers
c. Angiotensin-converting enzyme inhibitors
d. Phentolamine

Answer:

d. An α-blocker, such as phentolamine, will be the most rapid and effective antihypertensive therapy. Controlling blood pressure may forestall a cerebral hemorrhage.

82. Which is the effect of amphetamines on sleep?

a. Decreases proportion of nonrapid eye movement (NREM) stages 1 and 2
b. Decreases proportion of NREM stages 3 and 4
c. Decreases proportion of rapid eye movement (REM)
d. Displaces REM from nighttime to daytime

Answer:

c. Amphetamines not only reduce total sleep time, but they also suppress REM sleep.

83. What is the primary effect of opioids on respiration?

a. They reduce the respiratory rate.
b. They reduce the depth of respirations.
c. They increase the rate but reduce the depth of respirations.
d. They increase the depth and rate of respirations.

Answer:

a. Opioids primarily reduce the respiratory rate. In an overdose, opioids lead to respiratory arrest and pulmonary edema.

84. What is the effect of PCP–NMDA receptor interaction?

a. A PCP–NMDA receptor interaction stabilizes the ion channel.
b. It leads to an influx of negatively charged chloride ions, which hyperpolarizes the neuron.
c. It triggers an influx of calcium, which leads to excitotoxicity.
d. It prevents the influx of calcium that glutamate induces.

Answer:

d. Glutamate ordinarily triggers an influx of calcium, but a PCP–NMDA receptor interaction prevents it.

85. Which of the following is a common effect of marijuana?

a. A fatal reaction to overdose
b. Seizures
c. Strokes
d. Reduced REM sleep

Answer:

d.

86. Which of the following statements concerning nicotine is false?

a. It affects CNS cholinergic receptors.
b. Its receptors are located in the mesolimbic pathway.
c. Bupropion may help smokers through withdrawal because, like nicotine, it increases dopamine concentrations.
d. Nicotinic receptors are the predominant CNS receptors.
e. Nicotinic receptors are the predominant neuromuscular junction receptors.

Answer:

d. Although both muscarinic and nicotinic receptors are present in the CNS, muscarinic receptors are predominant. In the peripheral nervous system, nicotinic receptors predominate at the neuromuscular junction.

87. Which are four characteristic features of cocaine use?

a. Blocks reuptake of dopamine into presynaptic neurons
b. Agitation or delirium
c. Hypertension
d. Slowed respiratory rate
e. Stimulation of the area postrema
f. Miosis
g. Chorea in some cases

Answers:

a, b, c, g. In contrast, slowed respiratory rate, stimulation of the area postrema, and miosis are characteristic features of heroin or other opioid overdose.

88. Which five are potential complications of cocaine administration?

a. Cerebral hemorrhage
b. Cerebral anoxia
c. Seizures
d. Radial nerve palsy
e. Development or exacerbation of tics
f. Stereotypies
g. Psychotic thinking
h. Pulmonary edema

Answer:

a, c, e, f, g. Cerebral anoxia and radial nerve palsy may follow respiratory depression from opioids or other drugs that depress consciousness. Pulmonary edema frequently follows heroin, methadone, or other opioid overdose.

89. In comparing heroin to morphine in terms of their use in cancer-induced pain, which of the following are heroin’s advantages?

a. Like benzodiazepine, heroin has its own receptor.
b. Because it more rapidly penetrates the blood–brain barrier, it has a more rapid onset of action.
c. It does not induce vomiting.
d. It improves affect to a greater degree.

Answer:

b. Compared to morphine, heroin penetrates the blood–brain barrier more rapidly. Like other opioids, it attaches to the mu receptor. Its effects are virtually indistinguishable from morphine’s.

90. Which neurotransmitter imbalance probably underlies delirium?

a. Excessive dopamine activity
b. Deficient dopamine activity
c. Excessive ACh activity
d. Deficient ACh activity

Answer:

d. Delirium is most closely associated with an absolute or, compared to dopamine activity, relative ACh deficiency.

91. Which of these medicines is not like the others?

a. Apomorphine
b. Ropinirole
c. Pramipexole
d. L-dopa
e. Bromocriptine

Answer:

d. Although all these medicines alleviate the symptoms of Parkinson disease, only L-dopa is a dopamine precursor. The others are dopamine agonists.

92. In serotonin’s fluctuations during the sleep–wake cycle, when is its activity greatest?

a. Slow-wave sleep
b. REM sleep
c. Arousal
d. None of the above

Answer:

c.

93. In its fluctuations during the sleep–wake cycle, when is serotonin concentration lowest?

a. Slow-wave sleep
b. REM sleep
c. Arousal
d. None of the above

Answer:

b. Serotonin concentration falls during slow-wave sleep and almost disappears during REM sleep.

94. Which enzyme is most important in serotonin metabolism?

a. MAO-A
b. MAO-B
c. COMT
d. DOPA decarboxylase

Answer:

a. In general terms, MAO-A metabolizes serotonin and MAO-B metabolizes dopamine. Selegiline, the Parkinson disease medicine, inhibits MAO-B. In the doses that neurologists prescribe (10 mg/daily), patients do not develop hypertensive crises from tyramine-containing food. Also, because selegiline at that or lower dosage does not interfere with serotonin metabolism, it should not cause the serotonin syndrome.

95. Which of the following is not a manifestation of anticholinergic medicines?

a. Miosis
b. Tachycardia and hypertension
c. Dry skin and low-grade fever
d. Constipation and urinary retention
e. Toxic encephalopathy (with high doses)

Answers:

a. Because anticholinergic medications reduce parasympathetic activity, thereby allowing sympathetic activity to predominate, they dilate pupils, cause tachycardia and hypertension, and reduce bowel and bladder activity. At high concentrations, they interfere with CNS ACh transmission and cause confusion, hallucinations, and depressed sensorium. Pharmacologic agents that might cause toxic levels of anticholinergic activity include atropine, trihexyphenidyl, tricyclic antidepressants, and certain dopamine-blocking antipsychotic agents. Physostigmine, a cholinesterase inhibitor that crosses the blood–brain barrier, restores ACh activity.

96. Which of the following is a nicotinic ACh receptor agonist?

a. Varenicline
b. Bupropion
c. Donepezil
d. Selegiline

Answer:

a. Varenicline (Chantix) is an agonist of certain nicotinic ACh receptors. Bupropion is an antagonist of nicotinic ACh receptors. Donepezil enhances ACh activity by reducing cholinesterase, but not by interacting with ACh receptors. Selegiline inhibits MAO-B.

97. Which of the following is not a manifestation of medicines that increase sympathetic activity?

a. Asthma
b. Tachycardia and hypertension
c. Tremor
d. Large pupils

Answer:

a. Sympathomimetic medicines, such as epinephrine, abort asthma attacks. They cause tremor and “fight or flight” signs, such as tachycardia, hypertension, and large pupils. They also cause tremor. Psychoactive drugs that have sympathomimetic properties include cocaine, amphetamine, and PCP.

98. What is the mechanism of action of MDMA (ecstasy) in producing euphoria?

a. Dopamine release and blocked reuptake
b. Serotonin surge
c. Mild glutamate toxicity
d. Mu receptor stimulation

Answer:

b. The euphoria with MDMA use occurs because of a rapid release of presynaptic serotonin stores. MDPV, cocaine, and other stimulants increase dopamine activity. Opioids stimulate mu receptors.

99. Which is the most prevalent excitatory neurotransmitter?

a. Norepinephrine
b. ACh
c. Glutamate
d. Dopamine
e. GABA

Answer:

c.

100. When used in the treatment of Alzheimer disease, what is the mechanism of action of memantine?

a. It interferes with cholinesterase.
b. It antagonizes NMDA receptors.
c. It acts as ACh.
d. It dissolves amyloid.

Answer:

b. Unlike anticholinesterase therapy for Alzheimer disease, which attempts to preserve ACh by inhibiting cholinesterase, memantine antagonizes NMDA receptors.

101. Which of the following is untrue regarding oxybate (GHB)?

a. GHB rapidly induces deep sleep and profound amnesia.
b. GHB is a product of GABA metabolism.
c. GHB suppresses cataplexy.
d. GHB assists nighttime sleep in narcolepsy.
e. GHB increases dopamine activity.

Answer:

e. GHB reduces dopamine activity. A product of GABA metabolism, GHB induces nighttime sleep in narcolepsy. GHB is dangerous, as when sexual predators intoxicate potential victims.

102. The following medicines alleviate spasticity. Which one acts as an α2-adrenergic agonist?

a. Baclofen
b. Tizanidine
c. Dantrolene
d. Benzodiazepines

Answer:

b. Tizanidine (Zanaflex) acts as an α2-adrenergic agonist. Baclofen binds to the GABAB receptor, dantrolene acts directly on muscles, and benzodiazepines act on their receptors.

103. A 30-year-old man presented to a neurologist because of increasingly severe and prolonged low and middle back pain. When upright, he had hyperlordosis and limited range of movement about the low back and legs. He had begun to walk like a “tin soldier.” Extensive testing revealed antibodies to glutamic acid decarboxylase (GAD) in the serum and spinal fluid. What is the most likely diagnosis?

a. Parkinson disease
b. Tetanus
c. Stiff-person syndrome
d. Catatonia

Answer:

c. He has stiff-person syndrome, which neurologists previously called “stiff-man” syndrome. This disorder is often a paraneoplastic syndrome. It is associated with anti-GAD antibodies that impair the synthesis of GABA. Decreased GABA activity results in abnormally increased muscular tone.

104. Which of the following is untrue regarding hypocretins?

a. Hypocretin-1 and -2 are equivalent to orexin A and B.
b. They are inhibitory neuropeptides.
c. They are increased during wakefulness and REM sleep.
d. In normal individuals, specific cells in the hypothalamus synthesize hypocretins and secrete them into the CSF.
e. Narcolepsy-cataplexy patients lose hypocretin-producing hypothalamic cells and have little or no CSF hypocretin.

Answer:

b. Hypocretin-1 and -2, which are equivalent to orexin A and B, are excitatory neuropeptides. Their deficiency is a hallmark of narcolepsy-cataplexy.

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